普罗布考和抗氧化维生素不影响体外实验条件下内皮细胞的白细胞粘附

为探讨预防动脉粥样硬化的药物普罗布考,维生素C和维生素E是否抑制内皮细胞表面粘附分子表达和白细胞一内皮细胞的粘附,以及这种抑制是否通过影响核因子－kB的活性来实现的,在液体流动小室中进行细胞粘附实验。用ELISA方法测定内皮细胞粘附分子E－选择素的表达;用电泳迁移率分析测定内皮细胞核因子－kB的活性,经肿瘤坏死因子α刺激的内皮细胞核因子－B活性增加,粘附分子E－选择素的表达上调（是基础水平的3．5倍）,其表面HL60细胞的粘附增加（是基础水平的4－26倍）,而抗氧化剂PDTC使所有这些变化都受到抑制。PDTC浓度为18umol/L时对粘附分子E－选择素的表达呈最大半抑制;PDTC浓度为52umol/L时对内皮细胞表面HL60细胞的粘附呈最大半抑制,普罗布考,维生素C和维生素E对肿瘤坏死因子α诱导的粘附分子表达和HL60细胞与内皮细胞的粘附没有作用,对核因子－kB的活性没有影响,临床上常用的这三种抗氧化剂并未影响作为动脉粥样硬化始动机制之一的E－选择素介导的白细胞－内皮细胞粘附水平。     

补肾宁心方对单核-内皮细胞在动脉粥样硬化中相互作用的影响

目的　探讨补肾宁心方对动脉粥样硬化中单核 -内皮细胞相互作用的影响。方法　以培养人脐静脉内皮细胞 (HUVECs)作为靶细胞 ,在内皮细胞培养基中加入氧化型低密度脂蛋白 (ox- LDL)并在试验体系中加入灌服补肾宁心方的兔血清 ,收集内皮细胞条件培养基 ,作用于人单核细胞系 U937细胞 ,检测内皮细胞条件培养基中 MCP- 1的含量及内皮细胞表面粘附分子、细胞间粘附分子 - 1 (ICAM- 1 )、血管细胞粘附分子 - 1(VCAM- 1 )的表达 ,同时测定 U937细胞 CCR2、LFA- 1以及 VL A- 4 m RNA水平。结果　 ox- LDL显著升高内皮细胞条件培养基中 MCP- 1的含量 ,明显促进内皮细胞表面 ICAM- 1、VCAM- 1的表达 ,且在内皮细胞条件培养基作用下单核 U937细胞 CCR2、L FA- 1以及 VL A- 4 m RNA水平明显升高。如在试验体系中加入灌服补肾宁心方的动物血清 ,则 MCP- 1含量明显下降 ,内皮细胞表面 ICAM- 1、VCAM- 1的表达显著下调 (P<0 .0 1 ) ,且在条件培养基作用下单核 U937细胞 CCR2、LFA- 1以及 VLA- 4 m RNA水平明显下调。结论　补肾宁心方含药血清可能通过抑制内皮细胞分泌趋化因子、下调内皮细胞表面粘附分子的表达 ,抑制内皮细胞对单核细胞的趋化及相互粘附 ,从而发挥对血管内皮细胞的保护作用。     

霉酚酸酯抑制内皮细胞表面粘附分子的表达

目的 :观察霉酚酸酯 (MMF)对炎症因子刺激下内皮细胞表面粘附分子ICAM 1表达的影响。　 方法 :以TNFα(2 0 μg/L)刺激内皮细胞 ,细胞表面的ICAM 1蛋白表达以流式细胞术检测 ,内皮细胞ICAM 1mRNA表达采用逆转录 半定量PCR法进行测定。　 结果 :TNFα(2 0 μg/L)刺激内皮细胞 2 4h ,内皮细胞表面的粘附分子ICAM 1的蛋白和mRNA表达明显上升。MMF可以抑制内皮细胞的ICAM 1蛋白和mRNA的表达 ,这一抑制作用随着MMF剂量的增加而增强。　 结论 :MMF可以抑制内皮细胞粘附分子ICAM 1的表达     

阿托伐他汀对HMGB1诱导血管内皮细胞激活的影响

目的探讨阿托伐他汀能否抑制高迁移率族蛋白1(HMGB1)诱导的血管内皮细胞激活,阐明其潜在的分子机制。方法体外培养大鼠胸主动脉内皮细胞,分别用不同浓度的阿托伐他汀、HMGB1、TLR4特异性抑制剂CLI-095预处理内皮细胞,荧光定量分析中性粒细胞与内皮细胞的黏附活力;实时定量RT-PCR与Western blot分别检测TLR4、细胞间黏附分子1(ICAM-1)和E-选择素mRNA和蛋白的表达水平;电泳迁移率实验(EMSA)测定核因子κB(NF-κB)p65的DNA结合活性。结果阿托伐他汀(0.1～10μmol/L)呈剂量依赖性地抑制HMGB1诱导的血管内皮细胞活化。阿托伐他汀预处理能明显下调HMGB1诱导的TLR4 mRNA和蛋白表达水平(P均0.05);阿托伐他汀、CLI-095均能有效抑制HMGB1诱导的NF-κB p65的DNA结合活性以及ICAM-1和E选择素的表达水平(P均0.05)。结论阿托伐他汀可通过调节黏附分子(ICAM-1和E-选择素)的表达而显著抑制HMGB1诱导的血管内皮细胞活化效应,其机制可能与它抑制TLR4的表达及NF-κB激活有关。     

核因子-κB活性对BXSB狼疮小鼠脾脏自发性生发中心形成的影响

目的探讨核因子(NF)-kB活性对BXSB狼疮小鼠脾脏中自发性生发中心形成的影响及其机制。方法18只BXSB自发性狼疮小鼠随机分成对照组和吡咯二硫氨基甲酸酯(PDTC)干预组,PDTC组：隔日腹腔注射PDTC(120mg/kg体重)；对照组：隔日腹腔注射等量溶媒。持续8周结束实验。以电泳迁移率改变实验检测脾脏组织NF-kB活性,双标记流式细胞术检测脾脏B细胞CD154表达及生发中心B细胞凋亡,组织化学方法染色脾脏生发中心,并以图像处理系统半定量分析。结果PDTC显著抑制BXSB狼疮小鼠脾脏组织NF-kB活性,较对照组下降62．82%；BXSB狼疮小鼠脾脏组织可见自发性生发中心形成,抑制NF-kB活性能下调脾脏B细胞CD154表达、使其自发性生发中心形成受阻、促进生发中心B细胞凋亡。结论NF-KB过度活化可通过上调脾脏B细胞CD154的异常表达而促进自发性生发中心形成、并减少生发中心B细胞凋亡。由此,自发性生发中心形成过程中生成的自身反应性B细胞得以逃逸凋亡,分化成产自身抗体浆细胞。提示NF-kB可成为防治系统性红斑狼疮的一个作用靶点。     

氧化低密度脂蛋白通过血凝素样氧化低密度脂蛋白受体1诱导血管内皮细胞粘附分子的表达

目的探讨血凝素样氧化低密度脂蛋白受体1（LOX-1）在氧化低密度脂蛋白（ox—LDL）诱导血管内皮细胞粘附分子表达中的作用。方法用不同浓度ox-LDL培养人脐静脉内皮细胞（HUVECs）,用RrealtimeRT—PCR测定LOX-1 mRNA的表达;RT—PCR测定细胞间粘附分子1（ICAM-1）、血管细胞粘附分子1（VCAM-1）以及E选择素的mRNA表达;用Westernblot测定LOX-1、ICAM-1、VCAM-1以及E选择素蛋白的表达,观察ox-LDL对血管内皮细胞粘附分子表达的影响。HUVECs预先用聚肌苷酸[poly（I）]和爱兰苔胶处理,再用ox—LDL培养,再分别测定上述粘附分子的表达水平,比较加入LOX-1阻断剂前后粘附分子表达的变化。结果ox-LDL各剂量组皆可上调LOX-1、ICAM-1、E选择素的mRNA和蛋白表达（P〈0．01）,在10～50μm/ml剂量范围内呈现明显的剂量一效应关系（P〈0．01）,但ox—LDL对VCAM-1的表达没影响。HUVECs预先与250μg／ml的poly（Ⅰ）或爱兰苔胶作用2h,然后加入50μg/ml的ox—LDL作用24h。poly（Ⅰ）和爱兰苔胶都能抑制ox—LDL诱导的LOX-1、ICAM-1和E选择素的mRNA和蛋白表达水平,与未阻断组相比,差异皆有统计学意义（P〈0．01）。结论ox—LDL可以上调血管内皮细胞粘附分子的表达,LOX-1受体阻断剂可以部分阻断ox—LDL的上调作用,ox-LDL诱导血管内皮细胞粘附分子的表过是通过LOX-1介导的。     

大黄素对急性胰腺炎大鼠胰腺核因子-kB活化的影响

目的观察大黄素对急性胰腺炎(AP)大鼠胰腺组织核因子-kB(NF-kB)活化的影响,初步阐明大黄素治疗 AP 的分子作用机制。方法雄性 SD 大鼠采用持续输注雨蛙素(5 μg·kg~(-1)·h~(-1))法建立急性水肿性胰腺炎模型,分为注射后5、30min 及1、2、4、6 h 组,停止输注后6h 组;造模前2h 大鼠腹腔注射大黄素(10、30、100mg/kg)组及生理盐水对照组。采用电泳迁移率改变分析实验检测 NF-kB DNA 结合活性,Western blot 检测 NF-kB 抑制蛋白(ⅠkBs)的ⅠkBα和ⅠkBβ降解水平,Northern blot 检测 NF-kB 信号下游效应分子单核细胞趋化蛋白-1(MCP-1)和细胞间粘附分子-1(ICAM-1)基因表达。结果超生理剂量的雨蛙素可诱导大鼠胰腺 NF-kB 发生双相活化,活化高峰出现在雨蛙素注射30min 和4h 后,其相对面积灰度值分别为正常对照的(3.9±2.0)和(7.7±3.2)倍(n=4,P 值均<0.01)。大黄素10、30和100mg/kg剂量治疗组大鼠胰腺 NF-kB 活性较 AP 模型组分别下降45%,62%和84%(30min)和28%,74%和80%(4h,n=4,P 值均<0.01)。同时,大黄素(100mg/kg)可明显抑制雨蛙素诱导的胰腺ⅠkBα和ⅠkBβ蛋白降解(n=4,P 值均<0.01)。与其对 NF-kB 活化的抑制作用一致,大黄素剂量依赖性地抑制雨蛙素诱导的胰腺 MCP-1和 ICAM-1基因表达。结论大黄素可抑制胰腺内ⅠkBs/NF-kB 信号转导通路活化,从而抑制炎性细胞因子和粘附分子基因表达,发挥其对 AP 的治疗作用。     

氧化型低密度脂蛋白对血管内皮细胞ICAM-1 mRNA表达的影响

目的 探讨氧化型低密度脂蛋白(ox-LDL)对人血管内皮细胞表达细胞间粘附分子-1(ICAM-1)的影响。方法 采用血管内皮细胞株EAhy926培养，观察150mg／L的氧化型低密度脂蛋白作用在不同时程(0～36h)及不同终浓度(0～300mg／L)的氧化型低密度脂蛋白作用24h对细胞间粘附分子-1mRNA表达的影响。RT-PCR测定ICAM-1基因表达水平。结果 氧化型低密度脂蛋白可诱导培养血管内皮细胞表达细胞间粘附分子-1mRNA，并呈时间和剂量依赖性增加。结论 ox-LDL可以促进EAhy926细胞间粘附分子-1表达，ICAM-1可能参与氧化型低密度脂蛋白所致的动脉粥样硬化进程。     

辛伐他汀抑制糖基化终产物诱导心肌微血管内皮细胞炎性反应及机制探讨

目的观察羟甲基戊二酰辅酶A还原酶抑制荆辛伐他汀对糖基化终产物(AGEs)诱导心肌微血管内皮细胞(CMECs)表达单核细胞趋化因子1(MCP-1)、细胞间黏附分子1(ICAM-1)的抑制作用,探讨辛伐他汀在早期糖尿病心肌微血管炎性病变中的保护机制。方法将培养的CMECs用辛伐他汀预孵育6 h,加入400mg/L的外源性糖基化牛血清白蛋白共培养72 h,分为AGEs组和BSA对照组,分别采用ELISA法测定McP-1的表达;流式细胞仪测定ICAM-1的表达;RT-PCR法测定糖基化终产物特异性受体mRNA的表达;Western blot法检测内皮细胞表面特异性受体(RAGE)蛋白表达。结果与BSA对照组比较,AGEs组MCP-1、ICAM-1、RAGE mRNA及其蛋白表达明显增强,差异有统计学意义(P<0.05)。辛伐他汀预孵则显著抑制AGEs诱导的MCP-1、ICAM-1的表达,并在mRNA及蛋白水平下调RAGE蛋白的表达。结论辛伐他汀可能通过抑制AGEs-RAGE信号途径来发挥对糖尿病心肌微血管病变的保护作用。     

氧化应激在血管内皮细胞缺氧/再给氧损伤中的作用

目的探讨冠状动脉内皮细胞(CAEC)缺氧再给氧(H/R)损伤发生机制及抗氧化剂吡咯烷二硫氨基甲酸脂(pyrroli dinedithiocarbamate,PDTC)对它的影响。方法将体外培养的猪CAEC分为3组。对照组:未经处理;H/R组:将细胞作H/R处理;PDTC组:于培养液中加入PDTC而后作H/R处理。分别检测各组CAEC谷胱甘肽(GSH)、丙二醛(MDA)的含量及细胞间黏附分子-1(ICAM-1)的表达。结果在相应时间点,对照组细胞GSH、MDA的含量及ICAM-1表达无明显改变;H/R组及PDTC组细胞GSH含量明显低于对照组,而MDA的含量及ICAM-1表达明显增高,其中PDTC组细胞GSH含量又明显高于H/R组,MDA的含量及ICAM-1表达明显低于H/R组。结论H/R损害CAEC,使其GSH含量明显减少、MDA含量及ICAM-1表达明显增加;PDTC有效降低ICAM-1活性,减轻H/R损伤。提示氧化应激在血管内皮细胞缺氧-再给氧损伤过程中起重要作用。     

西罗莫司对缺氧/复氧诱导内皮细胞-中性粒细胞黏附的影响及机制

目的　探讨西罗莫司对缺氧 复氧后血管内皮细胞表面黏附分子的表达和中性粒细胞 内皮细胞黏附的影响及机制。方法　采用 β N 乙酰氨基己糖苷酶比色法检测黏附率 ,流式细胞术检测内皮细胞表面黏附分子E 选择素、细胞间黏附分子 1(ICAM 1)的表达 ,Fenton反应测定活性氧 (reactiveoxygenspecies,ROS)的含量 ,Western杂交法检测内皮细胞c JunN端激酶 (JNK)及核因子 κB[nuclearfactor κB ,NF κB(P6 5 ) ]蛋白的表达。结果　血管内皮细胞经缺氧 复氧处理后ROS释放增多 ,JNK及NF κB(P6 5 )蛋白表达增加 ,E 选择素、ICAM 1的表达上调 ,其表面中性粒细胞的黏附增加 ,西罗莫司显著抑制缺氧 复氧的上述作用。结论　西罗莫司抑制缺氧 复氧后血管内皮细胞与中性粒细胞的黏附 ,并可能通过抑制ROS、JNK、NF κB的信号转导途径实现     

Butyrate inhibits leukocyte adhesion to endothelial cells via modulation of VCAM-1

BACKGROUND: Leukocyte recruitment to areas of inflammation depends on Integrin-VCAM/ICAM interaction. Blocking the vascular cell adhesion molecule (VCAM-1) and the intracellular adhesion molecule (ICAM-1) may have therapeutic benefit for the inflammatory component of bowel disease. Notably, the induction of ICAM and VCAM is mediated by a nuclear factor kappaB (NF-kappaB)-dependent mechanism. We investigated whether the anti-inflammatory properties of butyrate are mediated via the modulation of VCAM and ICAM on human endothelial cells. METHODS: VCAM-1 and ICAM-1 expression on human endothelial cells upon tumor necrosis factor-alpha (TNF-alpha) stimulation was assessd by FACS analysis. A monocyte adhesion assay was performed to evaluate the relevance of a modulated CAM-expression. Electrophoretic mobility shift assays were applied to investigate NF-kappaB activation. RESULTS: The observed butyrate-associated inhibition of monocyte adhesion to endothelial cells is associated with an inhibition of NF-kappaB activation in human endothelial cells. In this context, the observed suppression of the TNF-alpha induced VCAM-1 expression is likely to play an essential role. CONCLUSIONS: Butyrate inhibits VCAM-1 mediated leukocyte adhesion to human endothelial cells. This inhibition may contribute to the anti-inflammatory effects of butyrate in patients with distal ulcerative colitis.     

Acute‐phase serum amyloid A stimulation of angiogenesis,leukocyte recruitment,and matrix degradation in rheumatoid arthritis through an NF‐κB–dependent signal transduction pathway

Objective

To examine the role of the acute‐phase protein serum amyloid A (A‐SAA) in regulating cell adhesion molecule expression, leukocyte recruitment, and angiogenesis in rheumatoid arthritis (RA).

Methods

Intercellular adhesion molecule 1 (ICAM‐1), vascular cell adhesion molecule 1 (VCAM‐1), and matrix metalloproteinase 1 (MMP‐1) expression was examined in RA fibroblast‐like synoviocytes (FLS) and human microvascular endothelial cells (HMVECs) using flow cytometry and enzyme‐linked immunosorbent assay techniques. Peripheral blood mononuclear cell (PBMC) adhesion to FLS/HMVECs was determined by flow cytometry. Angiogenesis was examined using a Boyden chemotaxis chamber and Matrigel tubule formation. NF‐κB/IκBα mediation of the effects of A‐SAA was investigated using a specific NF‐κB inhibitor and Western blotting.

Results

A‐SAA significantly enhanced the time‐ and dose‐dependent expression of ICAM‐1 and VCAM‐1 as effectively as interleukin‐1β/tumor necrosis factor α. A‐SAA promoted the adhesion of PBMCs to FLS and HMVECs. In addition, A‐SAA at 10 μg/ml and 50 μg/ml significantly increased endothelial cell tube formation by 69% and 207%, respectively. At 50 μg/ml and 100 μg/ml, A‐SAA increased HMVEC migration by 188 ± 54% and 296 ± 71%, respectively (mean ± SEM). A‐SAA–induced expression of VCAM‐1, ICAM‐1, and MMP‐1 was down‐regulated by NF‐κB inhibition. Furthermore, A‐SAA induced IκBα degradation and NF‐κB translocation, suggesting that its proinflammatory effects are mediated in part by NF‐κB signaling.

Conclusion

Our findings demonstrate the ability of A‐SAA to induce adhesion molecule expression, angiogenesis, and matrix degradation, mechanisms that are mediated by NF‐κB. Targeting A‐SAA and its signaling pathways may represent a new therapeutic approach in the treatment of RA.

     

Regulation of ICAM-1-mediated fibroblast-T cell reciprocal interaction: implications for modulation of gut inflammation.

BACKGROUND & AIMS: Immune-nonimmune cell interactions modulate mucosal immunity. We investigated the expression of adhesion molecules by intestinal fibroblasts, the effect of immune cell-derived factor on fibroblast binding of T cells, and the consequences of interfering with adhesion molecule expression on fibroblast-T cell interaction. METHODS: Expression of fibroblast intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 surface and messenger RNA (mRNA) was measured before and after exposure to immune cell-derived supernatants. Fibroblasts were treated with antibodies to ICAM-1 or VCAM-1, or ICAM-1 antisense oligonucleotide Isis 2302, before a T-cell adhesion assay. RESULTS: Fibroblast activation by immune cell-derived cytokines enhanced ICAM-1 and VCAM-1 surface expression and mRNA as well as adhesiveness for T cells. Blockade with neutralizing antibodies showed that binding was almost exclusively dependent on ICAM-1. Isis 2302 specifically reduced fibroblast ICAM-1 mRNA and dose-dependently inhibited ICAM-1 surface expression and T-cell binding. CONCLUSIONS: ICAM-1 is essential for intestinal fibroblast binding of T cells, a phenomenon that is efficiently and specifically disrupted by ICAM-1 antisense oligonucleotides. These observations emphasize the crucial regulatory role of fibroblasts in mucosal immunity and their potential as targets for therapeutic intervention in intestinal inflammation.     

Effects of antioxidants and NO on TNF-alpha-induced adhesion molecule expression in human pulmonary microvascular endothelial cells

Pro-inflammatory cytokines initiate the vascular inflammatory response via upregulation of adhesion molecules on the endothelium. Recent observations suggest that reactive oxygen intermediates may play a pivotal role in TNF-alpha signaling and upregulate gene expression. We therefore evaluated the effects of pyrrolidine dithiocarbamate (PDTC; 0.1 mM) and spermine NONOate (Sper-NO; 1 mM) on adhesion molecule expression and nuclear factor kappa B (NF-kappaB) activation induced by TNF-alpha (10 ng/ml) in cultured human pulmonary microvascular endothelial cells (PMVEC). Treatment of cells with TNF-alpha for 4 h significantly induced the surface expression of E-selectin and ICAM-1. Treatment with TNF-alpha for 8 h significantly induced the surface expression of E-selectin, ICAM-1 and VCAM-1. The upregulation of these adhesion molecules was suppressed significantly by pretreatment with PDTC or Sper-NO for 1 h. 8-Bromo-cyclic GMP (1 mM) had no such effect, suggesting that the NO donor's effect was non-cGMP-dependent. The mRNA expression of E-selectin, ICAM-1 and VCAM-1, and activation of NF-kappaB induced by TNF-alpha for 2 h were decreased significantly by the above two pretreatments. N-acetylcysteine (10 mM) and S-nitroso-N-acetylpenicillamine (1 mM) had little inhibitory effects on the cell surface and mRNA expression of these adhesion molecules stimulated by TNF-alpha. Treatment with TNF-alpha for 4 h enhanced HL-60 leukocyte adhesion to human PMVEC, the effect of which was inhibited significantly by pretreatment with PDTC or Sper-NO. These findings indicate that both cell surface and mRNA expression of adhesion molecules in human PMVEC induced by TNF-alpha are inhibited significantly by pretreatment with PDTC or Sper-NO, possibly in part through blocking the activation of NF-kappaB. Although our in vitro results cannot be directly extrapolated to the in vivo situation, they suggest a potential therapeutic approach for intervention in cytokine-mediated inflammatory processes in the human lung.     

Fk-appaB在动脉粥样硬化中的作用

目的　研究体内基因多显性转录核因子 (NF kappaB)在动脉粥样硬化疾病中病变的动脉内皮细胞中表达的情况及意义。方法　采用免疫组织化学染色S P法检测 30例动脉粥样硬化病变动脉血管和 30例正常成年人动脉血管内皮细胞的NF kappaBP6 5蛋白 ,细胞间粘附分子 1(ICAM 1)和血管内皮细胞粘附分子 1(VCAM 1)的表达水平。结果　 (1)与正常动脉血管内皮细胞相比较 ,动脉粥样硬化病变动脉血管内皮细胞NF kappaBP6 5蛋白 ,ICAM 1以及VCAM 1表达水平均呈显著性增强 (P<0 0 0 1)。 (2 ) 6 0例动脉血管内皮细胞检测数据提示NF kappaB蛋白表达和ICAM 1表达呈直线回归关系 (b =0 80 2 ,P <0 0 0 1) ;NF kappaBP6 5蛋白表达和VCAM 1表达也呈直线回归关系 (b =0 711,P<0 0 0 1)。结论　NF kappaB的激活导致动脉粥样硬化患者体内ICAM 1和VCAM 1表达增强 ,加速了动脉粥样硬化病变过程     

Statins prevent endothelial cell activation induced by antiphospholipid (anti–β2‐glycoprotein I) antibodies: Effect on the proadhesive and proinflammatory phenotype

Objective

To investigate the ability of statins, the inhibitors of the hydroxymethylglutaryl–coenzyme A reductase enzyme, to affect endothelial cell activation induced by anti–β₂‐glycoprotein I (anti‐β₂GPI) antibodies in vitro.

Methods

Human umbilical vein endothelial cell (HUVEC) activation was evaluated as U937 monocyte adhesion, E‐selectin, and intercellular adhesion molecule 1 (ICAM‐1) expression by cell enzyme‐linked immunosorbent assay and as interleukin‐6 (IL‐6) messenger RNA (mRNA) expression by RNA protection assay. E‐selectin–specific nuclear factor κB (NF‐κB) DNA‐binding activity was evaluated by the gel‐shift assay. HUVECs were activated by polyclonal affinity‐purified IgG, human monoclonal IgM anti‐β₂GPI antibodies, human recombinant IL‐1β, tumor necrosis factor α, or lipopolysaccharide (LPS).

Results

Fluvastatin reduced, in a concentration‐dependent manner (1–10 μM), the adhesion of U937 to HUVECs and the expression of E‐selectin and ICAM‐1 induced by anti‐β₂GPI antibodies as well as by cytokines or LPS. Another lipophilic statin, simvastatin, display similar effects but to a lesser extent than fluvastatin. The inhibition of E‐selectin expression exerted by fluvastatin was related to the impairment of NF‐κB binding to DNA. Moreover, the drug attenuated the expression of IL‐6 mRNA in HUVEC exposed to anti‐β₂GPI antibodies or cytokines. Incubation of HUVECs with mevalonate (100 μM), concomitantly with fluvastatin, greatly prevented the inhibitory effect of statin.

Conclusion

Endothelial activation mediated by anti‐β₂GPI antibody can be inhibited by statins. Because of the suggested role of endothelial cell activation in the pathogenesis of antiphospholipid syndrome (APS), our data provide, for the first time, a rationale for using statins as an additional therapeutic tool in APS.